This proposal is to investigate kinetics of transcorneal flux and intra-ocular fate of pilocarpine. Methodology and mechanism of flux enhancement is of prime import. Central is the use of a transport chamber to test drug transport across the rabbit cornea in a closed system under simulated physiological conditions, including temperature. Previous work has shown that pilocarpine flux efficiency is inversely related both to loading dose and retention of drug within the cornea. The "depot" effect and transcorneal flux inhibition are significantly reduced by mediation of various hydrogel polymer vehicles. Topically administered drugs of low lipid solubility are transported mainly by slow diffusion, but also by another mechanism which is more efficient and which is mobilized by hydrogel mediation, and which is probably both saturable and inhibited by high drug doses. Investigations continue with the purpose to determining the anatomical site and kinetics of flux inhibition and the possible therapeutic significance of intracorneal drug retention as a "reservoir". Vehicle mediation of carbachol is being tested (an effective but poorly penetrating cholinergic) to determine if pilocarpine kinetics can be applied to other drugs, to determine if carbachol effectiveness can be enhanced by such mediation, and to determine if carbachol is a competitive inhibitor of low-dose pilocarpine flux. Polymer characteristics are being studied to determine maximal effectiveness and elucidate the mechanism of the enhancement of flux with such mediation. Similar tests are being conducted for Timolol, since this beta adrenergic antagonist may be more useful than at present in drop form when mediated by hydrogels. Preliminary results suggest that the Timolol retained in the cornea may act in part as a therapeutic "reservoir", in contrast to pilocarpine.